Pigment epithelium-derived factor (PEDF) is a 50 kD secreted glycoprotein made by many cell types. It has been shown to be a potent inhibitor of pathologic angiogenesis by inducing endothelial cell apoptosis. We developed a mouse null for PEDF that spontaneously remodels the liver matrix, accumulates lipid, and demonstrates progressive fibrosis with increased vascularity. All animals develop dysplastic lesions or hepatocellular carcinoma (HCC). These changes were associated with activated hepatic stellate cells and increased levels of angiogenic inducers, VEGF, and leptin in the PEDF null liver. Moreover, a significant decrease in PEDF mRNA was evident when PPAR gamma was over-expressed in rodent livers and PEDF interacted with nuclear receptors suggesting that PEDF may be a new target gene for a hormone receptor family known to be important regulators of lipid metabolism. Preliminary testing of PEDF gene therapy in a xenograft rodent model appeared promising when hepatoma tumors were found to have markedly reduced levels of VEGF and increased tumor necrosis. These results led us to the hypothesis that loss of multifunctional PEDF in the liver triggers an imbalance in hepatocyte and stellate cell-derived extracellular factors, thus, promoting a highly angiogenic environment capable of supporting the growth of tumors. Using cultured hepatocytes, stellate cells and the PEDF null mouse model, we will explore changes in angiogenic activity, epithelial growth, and elucidate mechanisms by which tumor cells down-regulate PEDF. PEDF null mice will be crossed with leptin-deficient mice to better characterize the signaling pathways between PEDF, leptin, and VEGF. PEDF expression levels will be examined in human HCC to assess its utility as a tumor prognostic marker. Xenograft models of HCC will be treated with recombinant PEDF protein or with PEDF gene therapy to characterize the actions of PEDF on tumor growth. The interaction of PEDF and PPARgamma will be investigated by evaluating the functional activity of PPAR response elements in the PEDF gene and the nuclear signaling pathways explored. This proposed study has the potential to identify a novel signaling pathway in the pathogenesis of liver disease and it may validate PEDF gene therapy as a potent new agent to combat liver cancer.